Project Summary Non-communicable diseases including cardiovascular diseases, metabolic diseases and cancer are the leading causes of death in developed countries. These diseases are predicted to also be the leading causes of death in developing countries by 2020. Stemming the increase in the prevalence of these diseases will require a more detailed understanding of their etiology using a life course approach. Existing data linking early chemical and non-chemical stressors to these adult-onset diseases derives either from well-powered cross- section or retrospective cohort studies, or under-powered prospective cohorts with short follow-up. Epigenetic alterations?a mechanism by which genes respond to the environment?have been hypothesized to link observed associations between early stressors and multiple common diseases. However, prior cross-sectional and retrospective studies have lacked early life covariate data and specimens that would help to examine the links between early life stressors and later life disease. To address these knowledge gaps, in 2005-2011, we developed the pre-birth Newborn Epigenetics STudy (NEST) cohort comprising more than 2000 women, and followed their offspring until age 3-5 years. The NEST cohort has become a resource used by our group to identify novel associations between chemical and non-chemical stressors, and early signs of these non- communicable diseases, including cardiometabolic dysfunction. This resource has also been used to replicate novel findings by other groups, to pool with other cohorts to enhance statistical power, and to test new hypotheses by others. Our overarching goal for this application is to maintain this resource. This will be accomplished through the retention of trained staff with the critical skills to, (i) maintain and enrich the cohort by collecting additional data and specimens, (ii) develop and implement quality control and quality assurance protocols on existing and to-be-collected data and specimens, and, (iii) establish a comprehensive web-based database to increase our capability for data re-use and pooling with other cohorts to enhance statistical power. Direct web access will also simplify the process of data sharing with other birth cohorts and prepare our data for linkage. We will follow the cohort until age 11-17 years. This age range coincides with peri-puberty and puberty?developmental windows of heightened susceptibility to the non-communicable diseases under investigation. We also will link NEST data with identifiable Health System- and State-run medical records. Completing the proposed study will result in an enriched specimen repository with quality control and quality assurance, and annotated epidemiologic and clinical data. These data and specimens will facilitate rapid hypothesis testing by our group as well as data sharing and linkage with other cohorts to enhance statistical power. Data contributing to our understanding of the developmental origins of adult-onset non-communicable diseases are critical for guiding public health intervention efforts.